Effects of high dose alpha-1-acid glycoprotein on despiramine toxicity in rats

Tricyclic antidepressants are bound extensively to alpha-1-acid glycoprotein (AAG) in serum. It has been suggested that the extent of drug-protein binding may influence the magnitude of cardiotoxicity associated with tricyclic antidepressant overdose. To study this question, desipramine (DMI), 45 mg/kg, was administered i.p. to anesthetized rats, producing an increase in QRS duration of 86.4 ± 20.5% and a decrease in systolic blood pressure of 28.1 ± 13.2%. Groups of six rats then received human AAG, 2.2 g/kg i.v. over 30 min, 4.4 g/kg i.v. over 60 min or control infusions of albumin. The serum AAG concentration increased to 29 times normal after AAG, 2.2 g/kg, and 46 times normal after AAG, 4.4 g/kg. The serum DMI concentration did not change with albumin infusion but increased 4.7-fold (1.9 ± 0.7 to 9.0 ± 1.6 μg/ml) after AAG, 2.2 g/kg, and 6.7-fold (2.3 ± 0.5 to 15.7 ± 7.0 μg/ml) after AAG, 4.4 g/kg. AAG infusion at either dose had no effect on systolic blood pressure compared to albumin. Animals treated with AAG, 2.2 g/kg, had less QRS prolongation 30 min after AAG infusion than animals treated with albumin (41 ± 13% vs. 64 ± 8%, P < .01) but no difference in QRS duration was observed between groups after the higher dose (4.4 g/kg) of AAG or albumin. Cardiac DMI concentrations 90 min after AAG or albumin treatments did not differ. Equilibrium dialysis of untreated rat serum that was spiked to simulate AAG and DMI concentrations before and after AAG infusion suggested that AAG increased markedly the bound fraction of DMI in vivo from 80.9 ± 3.0% before AAG to 97.0 ± 0.3% after treatment, but did not alter the unbound drug concentration. We conclude that human AAG infusion increases markedly DMI binding in the serum of rats with DMI toxicity, but does not decrease substantially the unbound DMI concentration in serum, the cardiac DMI concentration or DMI cardiotoxicity. It is unlikely that changes in the binding of DMI to AAG exert an important influence on DMI toxicity.